Analgesic and sedative drugs are mostly used in an “off label” fashion in children. The
pharmacokinetic-pharmacodymamic (PK/PD) approach is useful in order to determine
the dose-concentration-response relationship and therefore the optimal dose regimens
in different populations. However, this approach has not been fully explored for all
analgesics and sedatives. This is mostly due to the complex and multidimentional
nature of pain, making it challenging to evaluate objectively their effect particularly in
neonates and infants. Hence, there is an important need for PK/PD studies in pain
and sedation. This thesis focuses on analysing clinical trial results on specific areas that
lack good quality PK/PD data in order to optimise the dose of analgesic and sedative
agents in children.
The studies described in this thesis aimed to address the following questions: what is
the optimal dose of fentanyl for procedural pain in preterm infants (NEOFENT study);
what is the adequate dose regimen of fentanyl and clonidine to provide an adequate pain
and sedation management in asphyxiated newborns receiving hypothermic treatment
(SANNI study); and finally what is the optimal dose of clonidine and midazolam in the
PICU (CloSed study). In order to address these questions, PK and PK/PD models
were developed in order to describe the relationship between drug concentration and
analagesic/sedative effect using pain and sedation scores. These models were used to
define target concentrations and perform simulations to determine the optimal dose.
The results of the NEOFENT study showed that three genetic variants had a
significant influence on the fentanyl clearance and suggested an IV dose of 2 µg/kg for
procedural pain in preterm infants. The results of the SANNI analysis showed that
the hypothermic treatment significantly decreased the clearance of both fentanyl and
clondine. Finally, the models developed for the CloSed and SANNI studies suggested
that the dose routinely prescribed in clinical practice should be increased in order to
provide an adequate pain and sedation management
